In the literature there are described a variety of pharmaceutical compositions for the treatment and prophylaxis of the above mentioned diseases.
It is known the compound 3-(4-methyl-1-piperazinil)-iminomethyl rifamycin SV-Rifampicin [U.S. Pat. No. 4,193,020], which is characterized by activity against Gram-positive and Gram-negative microorganisms and against Mycobacterium tbc.
It is known the compound [U.S. Pat. No. 5,095,108], 3-(4-cinnamyl-1-piperazinyl)-iminomethyl rifamycin SV with Formula Ia:
where
R═H and R1═CH3COO
which has been shown in in vivo tests, higher therapeutic effect in comparison to rifampicin, and considerably longer serum half-life and a low acute toxicity.
It is known the sodium salt of the above compound [U.S. Pat. No. 6,476,036], with formula Ib
where
R═Na and R1═CH3COO
which is characterized by good solubility in water, faster resorption and better pharmacokinetic properties in in vivo experiments.
Methods are known for the preparation of rifamycin derivatives, including the compound Ia, wherein the 3-formylrifamycin SV, dissolved in tetrahydrofuran, ethyl acetate, chloroform or a mixture of two of these solvents is condensed with an appropriately substituted N-aminopiperazin, then the reaction mixture was concentrated, and the product is recrystallized from an organic solvent, such as acetone or isopropanol [U.S. Pat. No. 4,193,920, U.S. Pat. No. 4,002,752, BG 48618]. A disadvantage of the known methods is the relatively low yield (from 55% to 80%), and the necessity of purifying the product by recrystallization, and further processing of the mother liquors, which greatly complicates the process. By applying the method they use large amounts of organic solvents, which create additional difficulties in regeneration and environment.
A significant disadvantage is the presence of residual solvents (tetrahydrofuran, chloroform, acetone, isopropanol) in the final product, which, due to specific structure of anzamycin molecule can not be removed even after extensive drying under reduced pressure. Quantities of these solvents, found by gas chromatography, remains above the limits set out in EP 5.0/5.4 Known is a method for preparing a sodium salt (compound Ib) [U.S. Pat. No. 6,476,036], which comprises reacting equimolar amounts of a compound Ia with sodium methanolate, ethanolate or isopropanolate in a medium of the corresponding alcohol. The product was isolated by distilling off the solvent under reduced pressure and recrystallization from isopropanol.
The method is not efficient enough, as to give a relatively low yield of the product, while there is a need for recrystallization, in addition, in the final product is observed presence of residual organic solvents whose quantities are above the limits set out in EP 5.0/5.4
The above mentioned patent application [U.S. Pat. No. 6,476,036] describes another process for the preparation of the sodium salt, which is carried out in aqueous medium, adding to the suspension of 3-formylrifamycin SV water solution of sodium hydroxide and the resulting aqueous solution was subjected to lyophilisation.
The yield in this case was almost quantitative, but due to strong alkaline reaction medium product contains a number of impurities and needs recrystallisation from isopropanol, which leads to a significant reduction in yield and the presence of residual solvents in final product A disadvantage of the known methods is the relatively low yield (from 55% to 80%), and the necessity of purifying the product by recrystallization, and further processing of the mother liquors, which greatly complicates the process. Another disadvantage of the method is the use of organic solvents in large quantities, which creates difficulties in their regeneration, respectively, while protecting the environment. Another major drawback is the presence of residual solvents (tetrahydrofuran, chloroform, acetone, isopropanol) in the final product, which, due to specific structure of anzamycin molecule can not be removed and after extensive drying under reduced pressure. Quantities of these solvents, found by gas chromatography, remains above the limits set out in EP 5.0/5.4
Due to low solubility of rifamycins in ethyl alcohol the use of ethanol leads to a falling of the finished product as a crystalline residue and its direct isolation by filtration, without the necessity of distilling off the solvent in advance. At the same time the ethanol makes it difficult to carrying out the condensation in a conventional manner. It is generally accepted to a solution of 3-formylrifamycin SV in tetrahydrofuran or chloroform to add a solution of N-substituted aminopiperazin. Using ethyl alcohol as the reaction medium, 3-formylrifamycin SV remains undissolved, and the reaction is carried out in suspension. This leads to incomplete operation of the process and the presence of unreacted 3-formylrifamycin SV in the final product, which requires purification by recrystallization.
There are not known formulations comprising 3-(4-cinnamyl-1-piperazinyl)-amino derivatives of 3-formylrifamycin SV, and 3-formylrifamycin S.